The degeneration and/or death of cells in the nervous system is a major factor in many diseases and medical conditions. Such diseases and conditions include traumatic brain injuries, traumatic spinal cord injuries, stroke, hypoxia or ischemia related to decreased neural perfusion secondary to cardiac arterial bypass graft surgery (CABG), Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurodegenerative diseases. It is of interest to prevent or decrease such cell death and degeneration and to minimize the loss of neural function.
Certain compounds are useful as neuroprotective agents. One such compound is insulin-like growth factor 1 (IGF-1) (Scheepens et al, WO00/13650). IGF-1 is a naturally occurring peptide that can decrease the binding of glutamate to the glutamate receptors of neurons (Bourguinon, U.S. Pat. No. 5,804,550). IGF-1 can also decrease neuronal degradation caused by damage and disease. IGF-1 is cleaved by proteolysis in vivo to give des1-3 IFG-1 and the N-terminal tripeptide Gly-Pro-Glu (GPE). GPE and analogues have been found to be neuroprotective (Gluckman et al, U.S. Pat. No. 6,187,906 incorporated herein by reference).
However, such peptides may not be ideal for the treatment of neural death and degeneration especially in conditions in which they are rapidly metabolised in vivo. There is a need for compounds that have neuroprotective and neuroregenerative properties and that are more metabolically stable, especially to enzymatic degradation.
The use of peptidomimetics to mimic the behaviour of biologically active peptides is common in the pursuit of a drug candidate. Peptidomimetics that are more metabolically stable and protease resistant than peptides are desirable, and they often adopt well-defined conformations. Cyclic structures can provide a rigid geometry that can be used to probe the bioactive conformation of a given peptide. This rigidity conformationally restricts the molecule and thus provides a method to design molecules with enhanced biological activity.